Plant-based diets in patients with chronic kidney disease

Abstract Dietary protein restriction has been considered to be a nutritional-related strategy to reduce risk for end-stage kidney disease among patients with non-dialysis-dependent chronic kidney disease (CKD). However, there is insufficient evidence to recommend a particular type of protein to slow down the CKD progression. Recently, various plant-based diets could demonstrate some additional benefits such as a blood pressure-lowering effect, a reduction of metabolic acidosis as well as hyperphosphatemia, and gut-derived uremic toxins. Furthermore, the former concerns about the risk of undernutrition and hyperkalemia observed with plant-based diets may be inconsistent in real clinical practice. In this review, we summarize the current evidence of the proposed pleiotropic effects of plant-based diets and their associations with clinical outcomes among pre-dialysis CKD patients.

Chronic kidney disease (CKD) remains a global public health concern that affects around 10% of the general population worldwide [1].As a consequence of impaired kidney function, patients with CKD are at higher risk of unfavorable outcomes, including cardiovascular disease-related death and all-cause mortality, and risk is particularly high among those with advanced CKD [2].Therefore, slowing CKD progression has the potential to lower risk of death and to prolong the time to end-stage kidney disease (ESKD) or kidney replacement therapy (KRT) [3].Dietary protein restriction has long been a mainstay of nutrition therapy to retard CKD progression by reducing urinary protein excretion and glomerular hyperfiltration [4].According to the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQI) 2000 nutrition guideline in CKD [5], lowering protein intake to 0.6 g/kg/d was recommended for patients with an estimated glomerular filtration rate (eGFR) of <25 mL/min/1.73m 2 to retard the progression of CKD.This guideline also mentioned that >50% of protein intake should be of high biological value, which is likely to be an animal protein in origin.However, the statement regarding a particular protein type has not been fully addressed by the updated KDOQI guideline in 2020 [6] due to insufficient evidence.
The interest in plant-based diets has increased over time because of their potential cardiovascular health benefits, such as the reduction of incidence of ischemic heart disease [7] and cardiovascular mortality [8] among the general population.In addition, plant-based diets demonstrate a favorable impact on kidney outcomes in patients with CKD due to their utility for managing CKD-related complications, including metabolic acidosis, hyperphosphatemia, and hypertension.This review article aims to focus on the use of plant-based diets in patients with pre-dialysis CKD and highlight their pleiotropic effects and potential concerns in clinical practice.

Different types of protein diet and kidney outcomes
Several previous studies revealed that a high protein intake increased the risk of glomerular hyperfiltration and had deleterious effects on kidney function in both the general population [9][10][11] and patients with pre-existing CKD [12,13].A high protein consumption leads to multiple abnormalities in renal hemodynamics, primarily from the vasodilation of afferent arteriole, followed by an increase in intraglomerular pressure, which results in proteinuria and glomerulosclerosis [14].At the cellular level, the effect of glomerular hyperfiltration may also promote abnormal mesangial cell signaling and overexpression of transforming growth factor β (TGF-β), causing interstitial inflammation and fibrosis [15].Furthermore, consuming excessive dietary protein has been linked to metabolic disorders, including metabolic acidosis [16,17] and hyperphosphatemia [18].Although the findings from the "Modification of Diet in Renal Disease" (MDRD) study failed to demonstrate effectiveness of a low protein diet (LPD) in retarding CKD progression over a 2-year duration [12], a reanalysis of that study suggested that the LPD demonstrated a reno-protective effect after implementation for a longer period of time [19].Additionally, most wellcontrolled trials [20,21] and meta-analyses [22][23][24] have consistently supported a benefit of dietary protein restriction on slowing CKD progression.Based on the aforementioned evidence, the updated KDOQI guidelines stated that "a protein-restricted diet strategy is recommended in stages 3-5 CKD."A LPD, approximately 0.6-0.8g/kg/d, is strongly recommended in metabolically stable patients with diabetic and non-diabetic CKD to reduce the risk of ESKD or death.Besides the quantity of protein consumed, awareness of its quality (animal or plant) has increased among CKD patients.However, the guideline did not address protein type due to insufficient evidence.
Earlier observational studies [25][26][27][28] have shown a positive correlation between animal-based diets, especially red meat consumption [29], and the development of new-onset proteinuria and incident CKD in the general population.A study by Kontessis et al. [30] revealed that consuming diets high in animal-based protein in healthy subjects led to a glomerular hyperfiltration-related higher level of proteinuria and eGFR than plant-based protein diets at the same amount of total daily protein intake.In their study, an acute protein load of meat consumption was significantly associated with an increase in fractional albumin clearance and renal plasma flow by 40% and 14%, respectively.In the Nurses' Health Study (NHS) [31], a high intake of non-dairy animal protein in participants with CKD and an eGFR between 50 mL/min/1.73m 2 and 88 mL/min/1.73m 2 were also significantly associated with a faster decline in eGFR of 1.2 mL/min/1.73m 2 [95% confident interval, CI; -2.3 to -0.3] per 10-g increase in animal protein intake.Likewise, several controlled trials [32,33] revealed that partial replacement of animal protein with plant protein among patients with CKD receiving angiotensin-converting enzyme inhibitors additionally reduced the degree of albuminuria by average 10%-20% when compared with baseline values in the replacement group with plant-based protein.
The ability of plant-based proteins to meet human nutrition requirements has been debated when compared with animal-based proteins.Emerging evidence indicates that the conventional definition of a high-biological protein is constrained.To measure protein quality, the protein digestibility-corrected amino acid score (PDCAAS) and digestible indispensable amino acid score (DIAAS) adopted by the Food and Agricultural Organization of the United Nations and World Health Organization (FAO/WHO) are currently the preferred methods.PDCAAS and DIAAS are used to measure the protein digestible quality based on both human amino acid requirements and digestibility quality.A PDCAAS score <0.75 indicates that the protein is suboptimal, and a DIAAS score >1.0 denotes that there may be an increased benefit for health [34,35].
Animal-based proteins appear to have both higher PDCAAS and DIAAS scores (>0.9) compared with plantbased proteins, which range from 0.4 to 0.9, as shown in Table 1.However, with an adequate diet and blending the proper combination, consuming protein from plants does not increase the risk of malnutrition [36].According to a metaanalysis by Rand et al. [37], healthy adults can meet their protein needs regardless of dietary protein sources, whether animal, vegetable, or mixed.Furthermore, data from realworld studies [38,39] also supported and emphasized that a concept of well-balanced and diversified plant-based diets, focusing on a high proportion of plant proteins and complex for essential amino acids, and none of the patients had nutritional deficiency after a 1-year follow-up.

Spectrum of plant-based dietary patterns and their benefits in CKD
In general, plant-based diets include high proportions of vegetables, grains, legumes, fruits, and nuts, with a reduction or elimination of animal product consumption (Figure 1).Whole, unprocessed plant-based foods are preferred to their highly processed forms.
Among patients with non-dialysis-dependent CKD, the PLAnt-DOminant low-protein diet (PLADO) has recently been proposed by Kalantar-Zadeh et al. [45].PLADO is defined as an LPD with at least 50% of protein from plants, preferably whole, unrefined, and unprocessed foods.Additional characteristics of PLADO include a relatively low consumption of salt (<3 g/d), a greater intake of dietary fiber (at least 25-30 g/d), and a sufficient intake of calories (30-35 kcal/kg/d).There are several putative mechanisms by which patients with CKD would benefit from plant-based diets, as shown in Table 2.

Metabolic acidosis
Unlike animal products, plant-based foods provide natural alkali in the form of citrate and malate, which can be converted   , lactovegetarian diet (excluding meat, fish, or poultry but including dairy), ovo-vegetarian diet (excluding meat, fish, or poultry but including eggs), lacto-ovo-vegetarian diet (excluding meat, fish, or poultry but including dairy and eggs), pescatarian diet (excluding meat or poultry but including fish) and omnivorous diet (containing all food groups).
carbohydrates, such as quinoa, tofu, grains, soya, legumes, sweet potatoes, and brown rice, is nutritionally sufficient without amino acid deficiency.A study by Barsotti et al. [40] illustrated that patients with CKD treated with a low-protein diet of 0.7 g/kg/d with mixed plant-protein content, particularly cereals and legumes, could reach minimal requirements to bicarbonate.Studies from Goraya and colleagues [46,47] supported that the correction of metabolic acidosis with administration of oral sodium bicarbonate or alkali-producing fruits and vegetables (FV) attenuated kidney injury in patients with hypertensive nephropathy.The amelioration of acid retention is partly explained by a reduction in tubulo-interstitial injury, as demonstrated by a decrease in urine TGF-β level.As compared with oral sodium bicarbonate tablets, dietary acid reduction with plant-based diets additionally reduced dietary sodium intake from alkali therapy, resulting in lower arterial blood pressure, and also promoted weight reduction after a 3-year follow-up period [47].

Hyperphosphatemia and elevated fibroblast growth factor 23 (FGF-23) level
Although most plant foods contain higher levels of phosphorus than animal foods, intestinal absorption of phosphate from plant sources, which is mostly in the form of phytate, does not exceed 50% due to the absence of human phytase activity [18].Moreover, the phosphate bioavailability of animal foods is typically higher (40%-80%) than that of plant foods, particularly when phosphorus-based preservatives are used for meat processing [48].In addition, similar results reported by Moe et al. [49] and Di Iorio et al. [50] showed that a vegetarian diet was associated with a significant reduction in serum phosphorus and FGF-23 levels in patients with CKD.

Gut dysbiosis and its uremic toxins
Plants are the source of dietary fiber that preferentially promotes the proliferation of saccharolytic bacteria.These bacteria can break down fiber and produce short-chain fatty acids (e.g., acetate, butyrate, and propionate), which improve epithelial barrier integrity and lessen bacterial translocation and inflammation.By contrast, animal-based protein diets appear to generate a nitrogen-rich environment and promote the absorption of gut-derived uremic toxins.Notably, higher intake of animal-based foods in omnivorous diets has been linked to higher levels of circulating trimethylamine N-oxide (TMAO).Recent evidence reveals that this small molecule uremic toxin promotes the acceleration of atherosclerosis [51].
A study of McFarlane et al. [52] demonstrated that in patients with CKD stages 3-4, a higher intake of healthy plant foods (high plant-based diet index [PDI]; a measure of adherence to a high-quality plant-based diet) and a habitual intake of dietary fiber resulted in lower serum levels of free p-cresyl sulfate and indoxyl sulfate.These two prototypes of protein-bound uremic toxins were associated with an increased risk of cardiovascular events and mortality in CKD patients [53][54][55].It is likely that consumption of a plant-based, fiber-rich dietary pattern may result in beneficial changes in the gut microbiota, which lead to better clinical outcomes in patients with CKD.

Hypertension
There are several possible explanations for the blood pressure reduction in plant-based foods.Plant-based diets, particularly vegetarian diets, have a beneficial effect on weight reduction and low rates of overweight and obesity due to their relatively high fiber, reduced fat, and low energy content [56,57].
A meta-analysis of controlled trials by Neter et al. [58] revealed that an average reduction of 5 kg of body weight significantly decreased systolic blood pressure by 4.4 mmHg.In particular, Less likely to cause hyperkalemia (high K + contents but increase bowel movement and K + excretion) K + , potassium; -, denotes a lack of sufficient evidence of their associations.CKD, chronic kidney disease.
FV are the main sources of potassium, nitrate, and fiber.It is hypothesized that high potassium and nitrate intake promotes vasodilation and improves endothelial function while inhibiting reactive oxygen species production and platelet aggregation [59,60].Also, a report by Tuttle et al. [61] indicated that patients with a preference for plant-based diets had high serum levels of histidine and threonine, which have been reported to be associated with an improvement in blood pressure control by decreasing central sympathetic output and increasing nitric oxide in the brain vasomotor center [62].

CKD progression
An analysis using data from the Third National Health and Nutrition Examination Survey (NHANES) suggested that a higher intake of FV, assessed by the food frequency questionnaire (FFQ), was associated with a lower risk of ESKD requiring KRT among patients with CKD [63].Compared with the highest quintile (eating FV 6 times/d), eating FV <2 times/d was associated with a statistically significant 41% higher risk of ESKD.Similarly, Lew et al. [29] revealed that red meat consumption was dose-dependently associated with higher risk of kidney failure, whereas substituting one serving of red meat with soy or legumes was associated with a 50.4% reduction in the risk of ESKD.A study by Dinu et al. [64] in a CKD population also showed that those consuming a lactoovo vegetarian diet had a significantly higher eGFR with a mean difference of 4.2 mL/min/1.73m² compared with those following the meat and fish-containing Mediterranean diet.Data from the Atherosclerosis Risk in Communities (ARIC) study among a community-based cohort of 15,792 middleaged adults [65] also reported that higher adherence to a healthy plant-based diet, particularly in the highest quintile of diet quality, assessed by a modified semiquantitative FFQ was associated with a slower annual eGFR decline (−1.46; 95% CI, −1.50 to −1.43 mL/min/1.73m²) compared with those in the lowest quintile of diet quality (−1.57; 95% CI, −1.6 to −1.43 mL/min/1.73m²; P for trend = 0.001).To assess the association between the source of dietary protein and eGFR decline, the Longitudinal Study of Ageing Women cohort [66] reported that higher intake of plant-sourced protein was associated with a slower decline in kidney function after adjusting for confounders including animal protein and energy intake.Each 10-g increase in protein intake from plants was associated with a reduction in the annual eGFR decline (0.12; 95% CI, 0.01-0.23)mL/min/1.73m 2 ), whereas intake of animalsourced protein was not associated with retardation of eGFR decline (0.01; 95% CI, −0.04 to 0.05 mL/min/1.73m 2 per a 10-g increase in animal protein).

Nutrient deficiency
Previous studies demonstrated that consumption of a plantbased, LPD with adequate calories and a variety of food groups did not increase the risk of protein energy wasting, monitored by body weight and serum biochemistry, in stable patients with CKD [45,[67][68][69].Because they maintained neutral nitrogen balance with sufficient calorie supply, these individuals maintained normal anthropometric estimates of lean body mass and nutritional status regardless of plantor animal-based food types.With regard to micronutrients, Neufingerl and Eilander.[70] found that healthy individuals following self-selected plant-based diets, especially vegan diets, for a duration of several years increased their risk of inadequacy of some essential micronutrients such as vitamin B12, vitamin D, iron, zinc, and iodine.Thus, careful planning with frequent monitoring and assessment of nutritional status is required for long-term consumption of plant-based diets, particularly vegetarian diets.In addition, education on diverse nutrient-dense plant foods, food fortification, and possibly supplementation should be individually emphasized.

Hyperkalemia
Some evidence indicates that plant-based diets are not associated with hyperkalemia in most patients with CKD, particularly CKD stages 3 and 4 [40,[71][72][73][74]. Concentrated potassium content (e.g., juice, sauce, and dried fruit), food additives, and preservatives, but not whole-food forms, are the main hidden sources of dietary potassium intake [75,76].It should be recognized that muscle-based animal products, such as meat and poultry, are also naturally high in potassium content.To reduce the potassium content, boiling and soaking (and discarding the water) are effective cooking methods, leading to a loss of 60%-80% of the potassium in several raw foods [77].Besides dietary potassium load, there are several factors, including potassium bioavailability, shift, and excretion, which affect serum potassium levels (Figure 2).Plant-based foods, particularly in their whole and unprocessed form, tend to have a lower potassium bioavailability (approximately 50%-60%) compared with animal-sourced (approximately 80%) or processed food products (nearly 100%) [67].Alkalization due to the presence of base-producing organic anions, including malate and citrate [78], combined with the enhanced insulin sensitivity [79] associated with plant-based dietary patterns may facilitate intracellular potassium shifts  [80].Due to its high fiber content, a plant-based diet facilitates gastrointestinal transition time, allowing more potassium to be excreted, and also reduces constipation [81].For these reasons, the risk of hyperkalemia from plant-based diets may have been previously overstated.Indeed, not all plant-based foods have the same potential to cause elevated serum potassium levels.

Conclusion
According to the principles of "precision nutrition," not all patients with CKD should be routinely prescribed a plantbased diet.Implementation of a plant-based diet as an option for patients with CKD for managing CKD-related complications and slowing CKD progression requires agreement between patient and health-care provider team, including at least a nephrologist and renal dietitian.A more flexible strategy, based on the patient's habits and preferences, tends to achieve better results.Furthermore, patient communication and motivation are crucial to improve their adherence.Patients should be counseled on eating well-balanced and diversified plant-based diets to achieve nutritional sufficiency.Further well-controlled randomized studies are needed to address knowledge gaps for the implementation of plant-based diets in real clinical practice.
Author contributions.All authors contributed substantially to data analysis.WW drafted the manuscript, PK and KLJ revised it critically for important intellectual content.All authors approve the final version submitted for publication and agree to be accountable for all aspects of the work and take responsibility for statements made in the published article.

*
The proportions of each food type may vary depending on the individual but all dietary patterns included high proportion of whole and unprocessed plant.

Figure 1 .
Figure 1.The plant-based dietary spectrum.From left (less flexible) to right (more flexible): vegan diet (including only plant-based items), lactovegetarian diet (excluding meat, fish, or poultry but including dairy), ovo-vegetarian diet (excluding meat, fish, or poultry but including eggs), lacto-ovo-vegetarian diet (excluding meat, fish, or poultry but including dairy and eggs), pescatarian diet (excluding meat or poultry but including fish) and omnivorous diet (containing all food groups).

Figure 3 .
Figure 3. Concept of protein restriction in CKD stages 3-5, focusing on both protein quantity, low-protein diet (0.6-0.8 g/kg/d) in order to slow down the CKD progression, and protein quality, plant-compared to animal-based protein in managing CKD-related complications.Adapted from [82].CKD, chronic kidney disease.

Figure 2 .
Figure 2. Effects of plant foods on serum potassium level, including potassium bioavailability, shift and loss.GI, gastrointestinal; K + , potassium.

Table 2 .
Overview of plant vs animal foods for management of CKD-related complications